Elsevier

Psychoneuroendocrinology

Volume 99, January 2019, Pages 174-182
Psychoneuroendocrinology

Post-exposure cortisol administration does not augment the success of exposure therapy: A randomized placebo-controlled study

https://doi.org/10.1016/j.psyneuen.2018.09.015Get rights and content

Highlights

  • Studied the effects of post-exposure cortisol administration on exposure therapy outcome.

  • Employed contextual changes to examine cortisol effects on fear renewal.

  • Post-exposure cortisol administration did not promote exposure therapy outcome.

  • Post-exposure cortisol administration led to a stronger fear renewal at long-term.

Abstract

Cortisol administration prior to treatment can promote the efficacy of exposure-based treatments in specific phobia: cortisol has been proposed to reduce fear retrieval at the beginning of exposure and to enhance the acquisition and consolidation of corrective information learned during exposure. Whether cortisol exerts a beneficial therapeutic effect when given after exposure, e.g., by targeting the consolidation of new corrective information, has not been addressed so far to date. Here, we examined whether post-exposure cortisol administration promotes fear reduction and reduces return of fear following contextual change in specific phobia. Furthermore, the effect of cortisol on return of fear following contextual change (i.e., contextual renewal) was assessed. Patients with spider phobia (N = 43) were treated with a single session of in-vivo exposure, followed by cortisol administration (20 mg hydrocortisone) in a double-blind, placebo-controlled study design. Return of fear was assessed with behavioral approach tests (BATs) in the familiar therapy context (versus a novel unfamiliar context) at one-month and seven-month follow-up assessment. Exposure was effective in reducing fear from pre-treatment to post-treatment (i.e., 24 h after exposure) on fear-related behavioral (approach behavior during the BAT), psychophysiological (heart rate during the BAT) and subjective (fear during the BAT, spider-fear related questionnaires) measures of therapeutic outcome, with no add-on benefit of cortisol administration. Cortisol had no effect on contextual renewal at one-month follow-up. However, in a subsample (N = 21) that returned to the seven-month follow-up, an adverse effect of cortisol on fear renewal was found, with cortisol-treated patients showing an increase in subjective fear at the final approach distance of the BAT from post-treatment to seven-month follow-up. These and previous findings underline the importance of considering the exact timing of cortisol application when used as an add-on treatment for extinction-based psychotherapy: post-exposure cortisol administration does not seem to be effective, but might promote fear renewal at the subjective level.

Introduction

Although exposure constitutes a very powerful treatment for anxiety and stressor-related disorders (Hofmann and Smits, 2008; Norton and Price, 2007; Otte, 2011; Ruhmland and Margraf, 2001a,b,c), treatment success varies widely among patients and relapse constitutes a frequent problem (Craske et al., 2006; Durham et al., 2012). Consequently, the identification of novel strategies that can enhance exposure therapy seems to represent a useful avenue of research to yield more enduring and stable treatment benefits.

Pharmacological administration of the stress hormone cortisol, the primary glucocorticoid in humans, has emerged as a promising approach to augment the efficacy of exposure-based treatments (for a review, see de Quervain et al., 2017). Precisely, cortisol has previously been shown to reduce pathological symptoms in specific phobia (Soravia et al., 2006) and post-traumatic stress disorder (Aerni et al., 2004; Suris et al., 2010). Most importantly, cortisol application prior to exposure has been found to enhance therapeutic outcome in spider phobia (Soravia et al., 2006, 2014), social phobia (Soravia et al., 2006) and height phobia (de Quervain et al., 2011).

Although various mechanisms can account for exposure-induced fear reduction and symptom improvement, fear extinction has emerged as one central candidate responsible for exposure-induced symptom relief (Craske et al., 2008, 2014). Research on the behavioral and neurobiological underpinnings of fear extinction has received great interest in the last few decades. Much of these data suggest that fear extinction does not erase the original fear memory but encompasses the formation of a new inhibitory memory trace that competes with the previously established fear memory trace (Bouton, 2004). Within that model, the memory-modulating characteristics of cortisol are ideally suited to facilitate exposure (de Quervain et al., 2017). Thus far, the evidence from exposure therapy studies suggests that cortisol facilitates therapeutic outcome by suppressing fear memory retrieval and by facilitating the consolidation of the corrective information (i.e., extinction) acquired during exposure at the same time (for reviews, see Bentz et al., 2010; de Quervain and Margraf, 2008; de Quervain et al., 2017). However, the putative mechanisms of action are hard to dissect because the (timing-dependent) effects of cortisol on the different memory stages (i.e., encoding, consolidation, retrieval) of the fear and extinction memory trace have not been assessed systematically in translational studies. In fact, previous studies administered cortisol prior to exposure (de Quervain et al., 2011; Soravia et al., 2014), which can potentially affect fear retrieval, encoding of the corrective information learned during exposure, as well as the consolidation of both the corrective and the fear memory. To our knowledge, no translational study has been conducted which examined the effects of cortisol application after exposure to specifically target consolidation processes. Apart from a mechanistic understanding, such an investigation might be especially relevant from a clinical perspective. If effective, cortisol may be selectively utilized after exposure to enhance only positive mastery experiences.

Another important issue which has been mainly neglected in previous translational studies relates to the role of cortisol in modulating relapse phenomena. Relapse prevention after successful exposure represents a major challenge in clinical settings. Again, the fear extinction model offers a plausible mechanism to understand relapse phenomena. Fear extinction is known for its context-specificity (Bouton, 2004). Hence, in the clinical context, extinguished fear can return when patients encounter their feared object in contexts different to the treatment context, a phenomenon termed fear renewal (Bouton, 2004). Pre-clinical human studies have shown that stress hormones both enhance or attenuate the generalization of extinction across contexts, depending on their timing (Hamacher-Dang et al., 2013, 2015; Meir Drexler et al., 2017; Merz et al., 2014, 2018). Despite the clinical relevance of transferring treatment-induced fear reduction to contexts beyond the therapeutic setting, translational studies investigating the effects of cortisol on fear renewal are lacking so far.

In the current study, spider-phobic individuals underwent a single session of in-vivo exposure, followed by cortisol or placebo administration in a randomized, double-blind study design. Precisely, we administered 20 mg hydrocortisone, a dosage that was effective in promoting therapeutic outcome in previous studies (de Quervain et al., 2011; Soravia et al., 2014). The aims of the present study were twofold: First, we examined whether cortisol augments exposure therapy outcome when administered after exposure. Since enhanced consolidation of new corrective learning (e.g., extinction learning) construes one potential explanatory mechanism for the beneficial effects of cortisol on exposure, post-session cortisol administration was expected to augment therapeutic success from pre- to post-treatment: the beneficial effects of cortisol (versus placebo) were presumed to be displayed either on the level of spider-fear related questionnaires and/or decreased avoidance, subjective fear and heart rate during a standardized behavioral approach test (see de Quervain et al., 2011). Second, by employing one-month and seven-month follow-ups, we assessed whether cortisol administration affects exposure-induced long-term fear reduction as well as the susceptibility to context-dependent fear renewal as a readout for the generalization of treatment effects. Based on preclinical studies in humans that have shown that stress application after fear extinction, the laboratory analog of exposure, can render the extinction memory context-dependent (Hamacher-Dang et al., 2015), we expected cortisol administration to reduce the generalization of exposure effects across contexts. Since the latter has not been assessed in the exposure setting, we propose that a stronger fear renewal at one-month and seven-month follow-up in participants treated with cortisol is dependent upon which fear indices are being considered during the behavioral approach tests, i.e., subjective fear ratings, changes in heart rate and phobic cognitions (see Mystkowski et al., 2002; Rodriguez et al., 1999).

Section snippets

Participants

Participants were recruited by newspaper advertisements, postings in social media networks and bulletin board notices at the campus of the Ruhr University Bochum. Participation was restricted to patients with spider phobia (according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition) with an age between 18 and 65 years. Diagnosis was ascertained with the short version of the diagnostic interview for mental disorders (Mini-DIPS; Margraf, 1994).

Pre-exposure participant characteristics

As shown in Table 1, the cortisol group was not different from the placebo group in each control variable (i.e., age, BMI, BDI-II, STAI-T, ERQ, GSE) and the proportion of males, OC women, and FC women. Importantly, both groups were comparable in their pre-treatment scores on the spider-fear related questionnaires (cf. Table 1), score on the BAT (BAT#1; placebo: M = 6.61, SD = 1.95; cortisol: M = 7.35, SD = 1.31; t(38.70) = 1.48, p = .15), subjective fear at the initial approach distance

Discussion

In the current study, we investigated whether cortisol promotes exposure therapy outcome when given after exposure. Furthermore, we tested the effects of post-exposure cortisol administration on long-term fear reduction and fear renewal. Exposure treatment was highly effective in reducing fear of spiders on the behavioral (BAT), subjective (spider fear-related questionnaires, fear at the initial and final approach distance), and physiological level (heart rate). However, compared to placebo,

Contributors

FR, AZ designed the study. FR conducted the study. FR, CJM, AZ analyzed the data. FR, CJM, OTW, JM, AZ interpreted the data. FR, AZ wrote the manuscript. All authors contributed to and approved the final version of the manuscript.

Role of the funding source

The study was supported by grants from the Deutsche Forschungsgemeinschaft (FOR 1581, project 9 to A.Z. and J.M.; SFB 874, project A1 to M.T; SFB 1280, project A13 to A.Z. and J.M., project A08 to M.T., project A09 to C.J.M. and O.T.W.). The funders had no role in study design, data collection and analysis, preparation of the manuscript and decision to publish.

Conflict of interest

The authors declare no conflict of interest.

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